1. Field of the Invention
The present invention relates to novel esculetin derivatives and pharmaceutical compositions, more particularly an agent for protecting cartilage, i.e., a chondroprotective agent.
2. Description of the Related Art
There are various types of arthropathy, for example, rheumatoid arthritis, rheumatic fever, and osteoarthritis. Many people particularly suffer from rheumatoid arthritis and osteoarthritis, and these diseases are considered the major types of arthropathy. There are congenital and secondary osteoarthritis, and further primary osteoarthritis caused by degeneration of the articular cartilage along with aging. Patients suffering from primary osteoarthritis have recently been increasing along with the increase in the population of the aged.
Although there are considerable differences of the causes and conditions between rheumatoid arthritis and osteoarthritis, the articular function becomes eventually obstructed by the destruction of the cartilage in both of rheumatoid arthritis and osteoarthritis.
The first choice of medicines for treatment of rheumatic diseases, such as rheumatoid arthritis, rheumatic fever, systemic lupus erythematosus, or osteoarthritis, are analgesic and anti-inflammatory agents, for example, aspirin or indomethacin. Further, gold compounds (for example, Shiosol), immunomodulators, steroids, or D-penicillamine is used as the medicine for treatment of rheumatoid arthritis.
The above conventional analgesic and anti-inflammatory agents, however, were not effective against the destruction of the articular cartilage, and in fact, sometimes exhibited adverse effect in the experiments using chondrocytes. Further, no function to suppress the destruction of articular cartilage was found in the above medicines for treatment of rheumatoid arthritis.
It was known that esculetin and 4-methylesculetin exhibit the function to reduce cholesterol level, strengthening the veins, and anti-oxidation (Japanese Examined Patent Publication No. 42-16626). Further, it was also known that diesters of 4-methylesculetin with carboxylic acids having 6 to 25 carbon atoms, particularly, diesters of caprylic, lauric or palmitic acid exhibit an effective anti-inflammatory action in the treatment of skin disease (FR 2276819). However, it was not known that the above esculetin and esculetin derivatives exhibit a function to suppress cartilage destruction.